Chimeric Antigen Receptor Macrophages Instead of T Cells
Chimeric antigen receptor T cell therapies have done well in the treatment of leukemias, and are being adapted for use with cancers that form solid tumors. A patient's own cells are engineered to bear a new synthetic receptor that matches a specific protein on the surface of cancerous cells, which encourages an effective immune response against the cancer. As researchers discuss here, an alternative to the continued use of T cells of the adaptive immune system is to apply chimeric antigen receptors to macrophages of the innate immune system instead.
Chimeric antigen receptor (CAR) T cell therapy has been a game-changer for blood cancers but has faced challenges in targeting solid tumors. Now researchers may have an alternative to T cell therapy that can overcome those challenges. Their research shows genetically engineering macrophages - an immune cell that eats invaders in the body - could be the key to unlocking cellular therapies that effectively target solid tumors. The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Most importantly, it centers around macrophages, which eat invading cells rather than targeting them for destruction the way T cells do.
Macrophages also have another key difference from T cells in that they are the body's first responders to viral infections. This has historically presented challenges in trying to engineer them to attack cancer, since macrophages are resistant to infection by the standard viral vectors used in gene and cell therapy. In fact, this anti-viral property carried another unexpected benefit. Macrophages are generally among the first cells to be drawn in by cancer, and they are exploited to help tumors instead of eating them. However, the research team showed that when the viral vector is inserted, not only do these engineered macrophages express the CAR, they also transform into highly inflammatory cells. This transformation allows macrophages to resist being co-opted by tumors. Researchers say CAR macrophages may also be able to stimulate the rest of the immune system as they attack, potentially opening the door to a greater immune response.
I'm sure this is already being worked on somewhere in mouse models, but using gene editing these CAR macrophages could be given the ability to screte inflammatory cytokines or fragments of immune checkpoint anitbodies, perhaps with gene expression under the control of a short lived small molecule drug.
Special delivery by "armored" CAR-T (2018)
https://stm.sciencemag.org/content/10/457/eaav0334
They could also add a second chimeric antigen receptor that uses a scorpion toxin to generally identifity cancer cells (for brain cancer):
https://www.genengnews.com/news/brain-cancer-car-t-cell-therapy-guided-by-scorpion-toxin-starts-first-human-trial/
"City of Hope scientists have started a first-in-man clinical trial to evaluate a chimeric antigen receptor (CAR) T cell therapy for glioblastoma (GBM) that uses a scorpion venom peptide called chlorotoxin (CLTX) to direct T cells to target brain tumor cells. The researchers have just published details of preclinical studies with the technology, which showed that treating mouse models of GBM using the CLTX-CAR T cells resulted in tumor regression, without evidence of off-target effects."